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Lung adenocarcinoma — clinical trials landscape

TL;DR — The lung-adenocarcinoma trial landscape is not one pipeline: it is a portfolio of genotype-specific inhibitor sequences, first-line combinations, perioperative strategies, antibody–drug conjugates, ctDNA/MRD-guided studies, CNS studies, and resistance baskets. Live ClinicalTrials.gov API queries on 2026-08-29 returned 490 recruiting/not-yet-recruiting/active-not-recruiting records explicitly indexed to “lung adenocarcinoma” and 2,429 under “non-small cell lung cancer”; these counts overlap and include trials not specific to this histology. Current pivots include first-line KRAS G12C combinations, subcutaneous versus intravenous amivantamab, repotrectinib against crizotinib, mutation-selective HER2 TKIs, and postoperative MRD intervention. Every NCT identifier and its status, phase, and enrollment field were re-fetched through the ClinicalTrials.gov v2 API during the 2026-08-29 audit; status remains a dated snapshot, not a permanent fact. Trial interpretation should separate randomized evidence, single-arm response cohorts, platform-screening denominators, and expansion cohorts.

Registry snapshot and method

Queries used ClinicalTrials.gov API v2 on 2026-08-29. “Active” below combines RECRUITING, NOT_YET_RECRUITING, and ACTIVE_NOT_RECRUITING.

Registry condition query Active Completed Interpretation
Non-Small Cell Lung Cancer 2,429 3,247 Broad mixed-histology universe; includes prevention, procedures, supportive care, and observational studies
Lung Adenocarcinoma 490 578 More specific but indexing-dependent; not a complete molecular-trial count

Counts should not be added because the sets overlap. Status and enrollment fields are sponsor-submitted registry data, not proof of recruitment at a particular site.

How to read the portfolio

Design What it can establish Common trap
Randomized phase III Comparative efficacy/safety under protocol Crossover and subsequent therapy can dilute OS
Single-arm registrational cohort Response rate and duration in rare genotype Historical controls and selected patients
Basket trial Activity across rare molecular states Mixing tumor types and variants
Platform trial Efficient molecular screening and cohort replacement Counting screened patients as treated evidence
MRD-guided trial Clinical utility of acting on ctDNA Treating prognostic validation as intervention proof
Real-world cohort Generalizability and rare safety Confounding by access and treatment selection

EGFR portfolio

NCT Study Phase/status on 2026-08-29 Design question
NCT06376084 Osimertinib with chemotherapy first line Active, not recruiting; n=532 Confirms/intends regional evidence for intensification
NCT03769103 Osimertinib + SRS vs osimertinib alone for brain metastases Active, not recruiting; phase 2; n=40 Whether upfront local CNS therapy adds benefit
NCT05256290 Silevertinib/BDTX-1535 in EGFR-mutant NSCLC/GBM Active, not recruiting; phase 1/2; estimated n=200 Mutation-selective next-generation EGFR inhibition
NCT04486833 Quaratusugene ozeplasmid + osimertinib after osimertinib progression Recruiting; phase 1/2; estimated n=158 Gene-therapy combination and resistance
NCT06156527 Lazertinib ± bevacizumab in EGFR-positive smokers Recruiting; phase 2; n=120 Angiogenesis intensification in a selected phenotype
NCT05801029 Osimertinib + amivantamab in common EGFR mutations Active, not recruiting; phase 2; n=60 Dual EGFR/MET blockade without chemotherapy
NCT05601973 Amivantamab-lazertinib-bevacizumab after third-generation TKI Active, not recruiting; phase 2; n=60 Triple targeted/antiangiogenic resistance strategy
NCT06784791 Preoperative amivantamab ± platinum-pemetrexed Recruiting; phase 2; n=20 Neoadjuvant EGFR-directed therapy and pathologic response
NCT04538664 PAPILLON: amivantamab + chemotherapy in exon-20 insertion Active, not recruiting; phase 3; n=308 Completed pivotal first-line comparison; ongoing follow-up
NCT05388669 Subcutaneous vs IV amivantamab with lazertinib Active, not recruiting; phase 3; n=418 Administration, reactions, PK, and efficacy

The published EGFR evidence path—from IPASS through FLAURA, ADAURA, and PAPILLON—shows why genotype and line of therapy must be explicit (PMIDs: 19692680, 29151359, 32955177, 37870976).

ALK, ROS1, and RET portfolio

NCT Driver/study Status/phase Question
NCT06682884 Neoadjuvant lorlatinib in stage IB–IIIB ALK-positive NSCLC Not yet recruiting; phase 2; n=25 Pathologic response and perioperative feasibility
NCT07374614 Iruplinalkib after lorlatinib in ALK-positive adenocarcinoma Recruiting; n=20 Post-lorlatinib sequencing
NCT06007937 Lorlatinib + ramucirumab Active, not recruiting; phase 1/2; actual n=9 Antiangiogenic combination feasibility
NCT06140836 TRIDENT-3: repotrectinib vs crizotinib Active, not recruiting; phase 3; n=190 Randomized first-line ROS1 comparison
NCT03093116 TRIDENT-1 repotrectinib basket Recruiting; phase 1/2; estimated n=500 ROS1/NTRK activity and resistance cohorts
NCT06315010 Repotrectinib in active ROS1-positive brain metastases Recruiting; phase 2; n=20 Prospective CNS activity
NCT06552234 Repotrectinib in frail/older ROS1-positive NSCLC Recruiting; phase 2; n=30 Generalizability beyond pivotal fitness
NCT04268550 Lung-MAP RET-fusion targeted treatment Active, not recruiting; phase 2; n=124 Cooperative-group RET pathway
NCT04819100 Selpercatinib after surgery/radiation Active, not recruiting; phase 3; n=152 Adjuvant RET inhibition
NCT03157128 LIBRETTO-001 Active, not recruiting; phase 1; n=857 Long-term and rare-cohort selective RET evidence

Published anchors are ALEX/CROWN for ALK, entrectinib/TRIDENT-1 for ROS1, and LIBRETTO-431 for RET (PMIDs: 28586279, 33207094, 31838015, 38197815, 37870973).

KRAS and RAS portfolio

NCT Study Status/phase Why it matters
NCT06793215 Divarasib + pembrolizumab vs pembrolizumab-platinum-pemetrexed Recruiting; phase 3; n=600 Moves G12C targeting into first line with direct standard comparator
NCT03600883 CodeBreaK 100 Completed; phase 1/2; actual n=713 Foundational sotorasib dose-expansion platform
NCT06162221 RAS(ON) inhibitors in RAS-mutant NSCLC Recruiting; phase 1/2; estimated n=616 Beyond GDP-state G12C inhibition and beyond G12C
NCT05132075 JDQ443 vs docetaxel Active, not recruiting; phase 3; n=95 Comparative later-line G12C evidence
NCT06917079 BBO-11818 in KRAS-mutant cancers Recruiting; phase 1; n=665 Broad KRAS-mutant early development
NCT07339839 Glecirasib + ivonescimab first line Not yet recruiting; phase 1/2; estimated n=42 KRAS plus immune/VEGF-bispecific strategy
NCT07198841 IBI351 + cetuximab in untreated G12C NSCLC Recruiting; phase 2; n=48 Feedback-blockade strategy

CodeBreaK 200 and KRYSTAL-12 show that randomized later-line comparisons are feasible; PFS benefit must be interpreted alongside toxicity, crossover, OS, and patient-reported outcomes (PMIDs: 36764316, 40783289, 39303400).

MET, HER2, and rare-driver portfolio

NCT Driver/study Status/phase Question
NCT06031688 Lung-MAP MET exon-14 cohort Recruiting; phase 2; n=56 Cooperative-group targeted pathway
NCT03175224 APL-101 in MET-altered solid tumors/NSCLC Recruiting; phase 2; n=497 Next MET inhibitor and resistance
NCT02414139 GEOMETRY mono-1 capmatinib Completed; phase 2; n=373 Pivotal METex14 evidence
NCT03944772 ORCHARD after first-line osimertinib Active, not recruiting; phase 2; n=247 Biomarker-matched resistance cohorts including MET
NCT05650879 ELVN-002 in HER2-mutant NSCLC Active, not recruiting; phase 1; n=198 HER2-selective TKI
NCT05246514 T-DXd in HER2-mutant NSCLC Active, not recruiting; phase 2; n=72 ADC efficacy and ILD characterization
NCT06760819 Sevabertinib in HER2-mutant solid tumors Recruiting; phase 2; n=111 Mutation-selective oral therapy
NCT07192068 Zanidatamab in HER2-altered tumors Recruiting; phase 2; n=105 Bispecific HER2 targeting across alteration states

These trials must keep mutation, amplification, overexpression, and exon skipping separate. Published anchors include GEOMETRY/VISION, DESTINY-Lung02, and zongertinib (PMIDs: 32877583, 32469185, 37694347, 40293180).

MRD and perioperative portfolio

NCT Study Status/phase Clinical-utility question
NCT04841811 APPROACH: MRD-guided maintenance in EGFR-mutant stage III Active, not recruiting; phase 3; n=192 Integrates local therapy, TKI, and MRD
NCT05822284 ctDNA-MRD after induction chemo-IO in stage IIIB–C Not yet recruiting; n=50 Prognostic monitoring in locally advanced disease
NCT05965024 MRD prediction after resection Recruiting; n=377 Sampling schedule and recurrence prediction
NCT06854939 MRD monitoring frequency after curative treatment Not yet recruiting; n=350 How often to sample and act
NCT06951646 CR1STAL-Adaptive ctDNA-guided escalation after durable IO response Recruiting; phase 2; n=70 Advanced-disease molecular escalation
NCT04585490 Personalized consolidation after chemoradiation/immunotherapy Recruiting; phase 3; n=48 Biomarker-directed stage III intensification
NCT06524427 RAVAR robot-assisted vs video-assisted lobectomy Recruiting; n=1,124 Surgical platform comparison

Observational MRD association is already strong (PMIDs: 28899864, 28445469, 34844976); these studies matter only if they show that acting on ctDNA improves outcomes.

Trial-design failure modes

Failure Consequence Better design
Molecular cohort too broad Dilutes allele-specific activity Predefine exact variant and resistance state
CNS exclusion Inflates apparent systemic benefit Include stable/active CNS cohorts with intracranial endpoints
ORR without duration Short responses appear equivalent Report duration, PFS, CNS progression, and subsequent therapy
Platform denominator hidden Screen failure and access invisible Report screened, assigned, treated, and evaluable separately
MRD positivity without action comparator Prognostic result mislabeled utility Randomize the action triggered by MRD
Post-progression crossover ignored OS interpreted naively Report treatment switching and estimands
Sponsor status treated as site availability Patients referred to closed sites Verify site-level recruitment directly

Open questions

  • Which first-line KRAS combination improves OS and quality of life without excess immune/hepatic toxicity?
  • Can randomized CNS-specific trials establish when radiation can be deferred for driver-positive disease?
  • Which MRD intervention improves cure rather than merely advancing relapse detection?
  • How should rare-driver trials pool globally while preserving allele, ancestry, and CNS detail?
  • Can platform trials report screening attrition and turnaround as co-primary implementation outcomes?
  • Which post-targeted-therapy resistance states need tissue rather than plasma for trial assignment?

References

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  3. Wu YL, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020. PMID 32955177
  4. Zhou C, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023. PMID 37870976
  5. Peters S, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017. PMID 28586279
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  11. de Langen AJ, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet. 2023. PMID 36764316
  12. Barlesi F, et al. Adagrasib versus docetaxel in KRAS(G12C)-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025. PMID 40783289
  13. Waterhouse DM, et al. Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation. Lung Cancer. 2024. PMID 39303400
  14. Wolf J, et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020. PMID 32877583
  15. Paik PK, et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med. 2020. PMID 32469185
  16. Goto K, et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023. PMID 37694347
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  21. Forde PM, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022. PMID 35403841
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